55,213 research outputs found

    Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.

    Get PDF
    Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with a role in cholesterol metabolism and cardiovascular disease. It has since emerged as a major risk factor (causative gene) for Alzheimer's disease and other neurodegenerative disorders. Detailed understanding of the structural features of the three isoforms (apoE2, apoE3, and apoE4), which differ by only a single amino acid interchange, has elucidated their unique functions. ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors), and apoE4 increases LDL levels (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors). ApoE4 also increases the risk for neurodegenerative diseases, decreases their age of onset, or alters their progression. ApoE4 likely causes neurodegeneration secondary to its abnormal structure, caused by an interaction between its carboxyl- and amino-terminal domains, called domain interaction. When neurons are stressed or injured, they synthesize apoE to redistribute cholesterol for neuronal repair or remodeling. However, because of its altered structure, neuronal apoE4 undergoes neuron-specific proteolysis, generating neurotoxic fragments (12-29 kDa) that escape the secretory pathway and cause mitochondrial dysfunction and cytoskeletal alterations, including tau phosphorylation. ApoE4-associated pathology can be prevented by small-molecule structure correctors that block domain interaction by converting apoE4 to a molecule that resembles apoE3 both structurally and functionally. Structure correctors are a potential therapeutic approach to reduce apoE4 pathology in both cardiovascular and neurological disorders

    Neuroregeneration in neurodegenerative disorders

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration - implantation of viable cells as a therapeutical approach.</p> <p>Discussion</p> <p>Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies.</p> <p>Summary</p> <p>In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.</p

    Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.

    Get PDF
    Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously

    Genetic Characterisation of Neurodegenerative disorders

    Get PDF
    Our global population is ageing and an ever increasing number of elderly are affected with neurodegenerative diseases, including the subjects of the studies in this work, Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). On strong evidence that several genes may influence the development of sporadic neurodegenerative diseases, the genetic association approach was used in the work of this thesis to identify the multiple variants of small effect that may modulate susceptibility to common, complex neurodegenerative diseases. It has been shown that the common genetic variation of one of these susceptibility genes, MAPT, that of the microtubule associated protein, tau, is an important genetic risk factor for neurodegenerative diseases. There are two major MAPT haplotypes at 17q21.31 designated as H1 and H2. In order to dissect the relationship between MAPT variants and the pathogenesis of neurodegenerative diseases, the architecture and distribution the major haplotypes of MAPT have been assessed. The distribution of H2 haplotype is almost exclusively in the Caucasian population, with other populations having H2 allele frequencies of essentially zero. A series of association studies of common variation of MAPT in PSP, CBD, AD and PD in different populations were performed in this work with the hypothesis that common molecular pathways are involved in these disorders. Multiple common variants of the H1 haplotypes were identified and one common haplotype, H1c, showed preferential association with PSP and AD. A whole-genome association study of PD was also undertaken in this study in order to detect if common genetic variability exerts a large effect in risk for disease in idiopathic PD. Twenty six candidate loci have been found in this whole-genome association study and they provide the basis for our investigation of disease causing genetic variants in idiopathic PD

    The thalamus as a putative biomarker in neurodegenerative disorders

    Get PDF
    Objective: This review provides a brief account of the clinically relevant functional neuroanatomy of the thalamus, before considering the utility of various modalities utilised to image the thalamus and technical challenges therein, and going on to provide an overview of studies utilising structural imaging techniques to map thalamic morphology in the spectrum of neurodegenerative disorders. Methods: A systematic search was conducted for peer-reviewed studies involving structural neuroimaging modalities investigating the morphology (shape and/ or size) of the thalamus in the spectrum of neurodegenerative disorders. Results: Whilst the precise role of the thalamus in the healthy brain remains unclear, there is a large body of knowledge accumulating which defines more precisely its functional connectivity within the connectome, and a burgeoning literature implicating its involvement in neurodegenerative disorders. It is proposed that correlation of clinical features with thalamic morphology (as a component of a quantifiable subcortical connectome) will provide a better understanding of neuropsychiatric dysfunction in various neurodegenerative disorders, potentially yielding clinically useful endophenotypes and disease biomarkers. Conclusions: Thalamic biomarkers in the neurodegenerative disorders have great potential to provide clinically meaningful knowledge regarding not only disease onset and progression, but may yield targets of and perhaps a way of gauging response to future disease-modifying modalities

    Wine Polyphenols and Neurodegenerative Diseases: An Update on the Molecular Mechanisms Underpinning Their Protective Effects

    Get PDF
    Alzheimer’s and Parkinson’s diseases are the most common age-related and predominantly idiopathic neurodegenerative disorders of unknown pathogenesis. Although these diseases differ in their clinical and neuropathological features, they also share some common aetiologies, such as protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Epidemiological, in vitro and in vivo evidences suggest an inverse correlation between wine consumption and the incidence of neurodegenerative disorders. Wine benefits are, in large part, attributable to the intake of specific polyphenols, which mediate cell function under both normal and pathological conditions. In this review, we aim to provide an overview of the role that wine polyphenols play in delaying neurodegenerative disorders. We discuss animal and in vitro studies in support of these actions and we consider how their biological mechanisms at the cellular level may underpin their physiological effects. Together, these data indicate that polyphenols present in wine may hold neuroprotective potential in delaying the onset of neurodegenerative disorders
    • …